DNA Mismatch Repair Interacts with CAF-1-and ASF1A-H3-H4-dependent Histone (H3-H4)2 Tetramer Deposition
DNA Mismatch Repair Interacts with CAF-1-and ASF1A-H3-H4-dependent Histone (H3-H4)2 Tetramer Deposition
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DOI：
10.1074/jbc.m115.713271
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发表时间：
2016-04-22
影响因子：
4.8
通讯作者：
Kadyrov, Farid A.
中科院分区：
文献类型：
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作者：
Blanko, Elena Rodriges;Kadyrova, Lyudmila Y.;Kadyrov, Farid A.
DNA错配修复（MMR）是维持基因组稳定性和保护人类免受几种癌症侵害所必需的。人类MMR发生在染色质环境中，但对MMR与染色质环境之间的相互作用知之甚少。先前的研究表明，MMR与新合成的DNA在核小体中的复制偶联组装一致。复制偶联核小体组装的第一步是caf -1依赖性组蛋白（H3-H4）(2)四聚体沉积，这一过程涉及ASF1A-H3-H4复合物。在这项工作中，我们使用重组的人体系统来研究MMR与caf1 -和asf1a -H3-H4依赖性组蛋白（H3-H4）(2)四聚体沉积之间的相互作用。我们发现MutS α抑制caf1 -和asf1a - h3 - h4依赖性的DNA错配包装成四体。这一发现支持了MMR发生在DNA错配被包装成四体之前的观点。我们的实验还揭示了caf1 -和asf1a -H3-H4依赖性组蛋白（H3-H4）(2)四聚体的沉积不会干扰MMR反应。此外，我们已经确定，在DNA聚合酶δ (Pol δ)-和DNA聚合酶epsilon （Pol epsilon）依赖的MMR反应中发生的不必要的不连续链降解被caf1 -和asf1a -H3-H4依赖的组蛋白（H3-H4）(2)四聚体沉积抑制。这些数据表明，caf1 -和asf1a -H3-H4依赖性组蛋白（H3-H4）(2)四聚体的沉积与MMR兼容，并保护不连续的子链免受MMR机制不必要的降解。
DNA mismatch repair (MMR) is required for the maintenance of genome stability and protection of humans from several types of cancer. Human MMR occurs in the chromatin environment, but little is known about the interactions between MMR and the chromatin environment. Previous research has suggested that MMR coincides with replication-coupled assembly of the newly synthesized DNA into nucleosomes. The first step in replication-coupled nucleosome assembly is CAF-1-dependent histone (H3-H4)(2) tetramer deposition, a process that involves ASF1A-H3-H4 complex. In this work we used reconstituted human systems to investigate interactions between MMR and CAF-1- and ASF1A-H3-H4-dependent histone (H3-H4)(2) tetramer deposition. We have found that MutS alpha inhibits CAF-1- and ASF1A-H3-H4-dependent packaging of a DNA mismatch into a tetrasome. This finding supports the idea that MMR occurs before the DNA mismatch is packaged into the tetrasome. Our experiments have also revealed that CAF-1- and ASF1A-H3-H4-dependent deposition of the histone (H3-H4)(2) tetramers does not interfere with MMR reactions. In addition, we have established that unnecessary degradation of the discontinuous strand that takes place in both DNA polymerase delta (Pol delta)- and DNA polymerase epsilon (Pol epsilon)-dependent MMR reactions is suppressed by CAF-1- and ASF1A-H3-H4-dependent deposition of the histone (H3-H4)(2) tetramers. These data suggest that CAF-1- and ASF1A-H3-H4-dependent deposition of the histone (H3-H4)(2) tetramers is compatible with MMR and protects the discontinuous daughter strand from unnecessary degradation by MMR machinery.